PROJECT SUMMARY OVERALL The mission of The Jackson Laboratory Cancer Center (JAXCC) is to discover precise genomic solutions for cancer by making basic discoveries with human impact. Committed to our role as a basic research Cancer Center, we harness our transdisciplinary strengths in complex genetics and functional genomics to achieve this goal. Organized in a single research program, Genetic models for precision cancer medicine, the 53 full members combine the JAXCC's unique capabilities to model human cancers in mice with innovations in genomic and computational analytics of human cancers to attack this broad problem. From RNA biology to chromatin dynamics, from organismal to in silico models of cancer, from panels of genetically diverse strains to humanized mice, from single cell genomics to Patient Derived Xenografts, from genomic engineering technologies to genomic diagnostics?The JAXCC brings advanced technologies to bear on persistent cancer problems through collaborative partnerships with clinical investigators. Since 2013, we achieved unprecedented growth with 22 new members with expertise in immunology, computational biology, genomic technologies, epigenetics, microbiome, tumor microenvironment, and clinical genomics. The Shared Resources (Cancer Model Development Resource, Computational Sciences, Genetic Engineering Technologies, Genome and Single Cell Technologies, and Phenotyping Technologies) provide comprehensive support for this wide range of research. The collaborative environment, access to powerful technologies, and our use of Developmental Funds has yielded significant advances: in the past 5 years, we have more than doubled our funding from NCI and other cancer agencies and increased our overall intra-programmatic grant collaborative rate from 21% to 47%. Our translational impact includes development of therapeutics exploiting genomic instability; our role as a discovery engine for SWOG and our new community cancer genomic education initiative, the Maine Cancer Genomics Initiative. In the next five years, the JAXCC will harness the collective energy of our expanded Cancer Center. We will identify origins and the consequences of complex structural genomic alterations in cancer; we will craft genetically complex models of cancer to uncover the systems biology of the disease; we will explore the cellular dynamics of primary cancer cells in culture to uncover genetic causes of therapeutic insensitivity; and we will explore tumor-microenvironment interactions through in vivo and in vitro tissue reconstructions. Our goal in the next grant cycle is to bring several diagnostics and therapeutics to clinical development. In addition, we will establish a Cancer Education and Career Enhancement core that supports a continuum of learning for students, trainees, early career investigators and the Maine community oncology care providers. Our focus on complex genetics and functional genomics, the scale of our model creation and experimentation, and the integration of our diverse talents make the JAXCC a unique enterprise.